Advanced Hepatobiliary Cancers Research Articles

The State of Systematic Therapies in Clinic for Hepatobiliary Cancers.

Hepatobiliary cancer (HBC) includes hepatocellular carcinoma and biliary tract carcinoma (cholangiocarcinoma and gallbladder carcinoma), and its morbidity and mortality are significantly correlated with disease stage. Surgery is the cornerstone of curative therapy for early stage of HBC. However, a large proportion of patients with HBC are diagnosed with advanced stage and can only receive systemic treatment. According to the results of clinical trials, the first-line and second-line treatment programs are constantly updated with the improvement of therapeutic effectiveness. In order to improve the therapeutic effect, reduce the occurrence of drug resistance, and reduce the adverse reactions of patients, the treatment of HBC has gradually developed from single-agent therapy to combination. The traditional therapeutic philosophy proposed that patients with advanced HBC are only amenable to systematic therapies. With some encouraging clinical trial results, the treatment concept has been revolutionized, and patients with advanced HBC who receive novel systemic combination therapies with multi-modality treatment (including surgery, transplant, TACE, HAIC, RT) have significantly improved survival time. This review summarizes the treatment options and the latest clinical advances of HBC in each stage and discusses future direction, in order to inform the development of more effective treatments for HBC.

Techniques and status of hepatic arterial infusion chemotherapy for primary hepatobiliary cancers.

Primary hepatobiliary cancers (PHCs), which mainly include hepatocellular carcinoma (HCC) and biliary tract cancers (BTCs), are mostly diagnosed in the advanced stage and are not candidates for curative surgery or ablation, resulting in a dismal prognosis. Targeted therapies with or without programmed death receptor 1 (PD-1)/PD-L1 inhibitors have been incorporated into first-line treatments for advanced HCC. Systemic chemotherapy is still the mainstay treatment for advanced BTCs, and combining it with PD-1/PD-L1 inhibitors has resulted in prolonged patient survival. Intra-arterial therapies, including trans-arterial chemoembolization, selective internal radiation therapy, and hepatic arterial infusion chemotherapy (HAIC), have been explored and used for advanced hepatobiliary cancers for many years with positive results, particularly when combined with systemic treatments. Recently, an increasing number of phase II/III trials have demonstrated the efficacy and safety of HAIC for the treatment of advanced HCC with portal vein tumor thrombosis and/or a large tumor burden, for the neoadjuvant and adjuvant treatment of HCC with high-risk factors, and for treating advanced intrahepatic and perihilar cholangiocarcinoma. However, the techniques and regimens used for HAIC are diverse and differ greatly between various regions and centers worldwide. This review focuses on these diverse techniques and regimens, as well as the updated evidence on HAIC regarding the treatment of PHCs.

Anticancer Drugs Compared to No Anticancer Drugs in Patients with Advanced Hepatobiliary Cancer: A Mapping Review and Evidence Gap Map.

Despite being commonly recommended, the impact of anticancer drugs (ACDs) on patient-important outcomes beyond survival for advanced hepatobiliary cancers (HBCs) may not have been sufficiently assessed. We aim to identify and map the evidence regarding ACDs versus best supportive care (BSC) for advanced HBCs, considering patient-centered outcomes. In this mapping review, we included systematic reviews, randomized controlled trials, quasi-experimental, and observational studies comparing ACDs (chemotherapy, immunotherapy, biological/targeted therapy) versus BSC for advanced HBCs. We searched MEDLINE (PubMed), EMBASE (Ovid), Cochrane Library, Epistemonikos, PROSPERO and clinicaltrials.gov for eligible studies. Two reviewers performed the screening and data extraction processes. We developed evidence maps for each type of cancer. We included 87 studies (60 for advanced liver cancer and 27 for gallbladder or bile duct cancers). Most of the evidence favored ACDs for survival outcomes, and BSC for toxicity. We identified several evidence gaps for non-survival outcomes, including quality of life or quality of end-of-life care. Patient-important outcomes beyond survival in advanced HBCs are insufficiently assessed by the available evidence. Future studies need to address these gaps to better inform decision-making processes.

Advances in medical treatment of advanced hepatobiliary and pancreatic cancer in 2022

AbstractThis article summarizes the drug therapy progress of advanced hepatocellular carcinoma, biliary tract cancer, and pancreatic cancer in 2022, including chemotherapy, molecular targeted therapy, and immunotherapy, to provide reference information for current clinical treatment and future clinical research, and to better improve prognosis and quality of life in patients with hepatobiliary and pancreatic cancer.

Systemic Oncological Treatments versus Supportive Care for Patients with Advanced Hepatobiliary Cancers: An Overview of Systematic Reviews.

The trade-off between systemic oncological treatments (SOTs) and UPSC in patients with primary advanced hepatobiliary cancers (HBCs) is not clear in terms of patient-centred outcomes beyond survival. This overview aims to assess the effectiveness of SOTs (chemotherapy, immunotherapy and targeted/biological therapies) versus UPSC in advanced HBCs. We searched for systematic reviews (SRs) in PubMed, EMBASE, the Cochrane Library, Epistemonikos and PROSPERO. Two authors assessed eligibility independently and performed data extraction. We estimated the quality of SRs and the overlap of primary studies, performed de novo meta-analyses and assessed the certainty of evidence for each outcome. We included 18 SRs, most of which were of low quality and highly overlapped. For advanced hepatocellular carcinoma, SOTs showed better overall survival (HR = 0.62, 95% CI 0.55-0.77, high certainty for first-line therapy; HR = 0.85, 95% CI 0.79-0.92, moderate certainty for second-line therapy) with higher toxicity (RR = 1.18, 95% CI 0.87-1.60, very low certainty for first-line therapy; RR = 1.58, 95% CI 1.28-1.96, low certainty for second-line therapy). Survival was also better for SOTs in advanced gallbladder cancer. No outcomes beyond survival and toxicity could be meta-analysed. SOTs in advanced HBCs tend to improve survival at the expense of greater toxicity. Future research should inform other patient-important outcomes to guide clinical decision making.

Early Experience of Combining Immune Checkpoint Inhibitor and Radiotherapy in Heavily Pretreated Hepatobiliary Cancer

<h3>Purpose/Objective(s)</h3> Promising therapeutic results of immune checkpoint inhibitor (ICI) have been reported in various solid tumors. Radiotherapy (RT) is known to enhance the immunogenic effect. The immunogenic effect of RT is expected to improve the therapeutic effect of ICI. In this study, we aimed to investigate the efficacy and toxicity of combining ICI and RT in hepatobiliary cancer. <h3>Materials/Methods</h3> Patients who received RT and ICI combination therapy for hepatobiliary cancer from January 2020 to December 2021 were retrospectively reviewed. Baseline patient characteristics such as age at diagnosis, stage, previous treatment, radiation dose, tumor volume, and lymphocyte count were recorded. The primary endpoints were in-field and out-field control rate. The secondary endpoint was treatment-related toxicities. Overall survival and progression-free survival were also evaluated. The disease control rate and survival were assessed using the Kaplan-Meier method. <h3>Results</h3> In total, 20 patients and 42 treated lesions were included for analysis. The median follow-up period was 6.2 months (range 2.4 – 23 months). Of the 20 patients, 15 were diagnosed hepatocellular carcinoma (75.0%). Sixteen patients had distant metastasis (80.0%). Various treatments were administered to the patients prior to ICI and RT combination treatment. The 6-month overall survival and progression-free survival was 62.8% and 31.5%, respectively. The 6-month in-field control rate was 71.8% and 6-month out-field control rate was 30.2%. Higher BED (≥ 90 Gy) was a significant prognostic factor for both in-field and out-field control, and lymphopenia (≤ 800 /μL) at the time of RT start was a poor prognostic factor for outfield control. Fractional dose of less than 5 Gy showed improved in-field control. Treatment related toxicity occurred in 11 patients (55.0%). The most frequent adverse event was GI disorders such as esophagitis (n=3) and epigastric pain (n=3). Patients who experienced treatment-related toxicity were well recovered after conservative care. There was no grade 3 or 4 toxicity. <h3>Conclusion</h3> The combination of ICI and RT showed substantial efficacy with acceptable toxicity in heavily pretreated advanced hepatobiliary cancer patients. Dose per fraction of less than 5 Gy may be appropriate for better efficacy in future study of combining ICI and RT. The results of this study provide a basis for future prospective study in hepatobiliary cancer.

Early experience of combining immune checkpoint inhibitor and radiotherapy in heavily pretreated hepatobiliary cancer.

457 Background: Promising therapeutic results of immune checkpoint inhibitor (ICI) have been reported in various solid tumors. Radiotherapy (RT) is known to enhance the immunogenic effect. The immunogenic effect of RT is expected to improve the therapeutic effect of ICI. In this study, we aimed to investigate the efficacy and toxicity of combining ICI and RT in hepatobiliary cancer. Methods: Patients who received RT and ICI combination therapy for hepatobiliary cancer from January 2020 to April 2021 were retrospectively reviewed. Baseline patient characteristics such as age at diagnosis, stage, previous treatment, radiation dose, tumor volume, and lymphocyte count were recorded. The primary endpoints were in-field and out-field control rate. The secondary endpoint was treatment-related toxicities. Overall survival and progression-free survival were also evaluated. The disease control rate and survival were assessed using the Kaplan-Meier method. Results: In total, 17 patients and 35 treated lesions were included for analysis. The median follow up period was 5.5 months (range 2.4 – 19.8 months). Of the 17 patients, 14 were diagnosed hepatocellular carcinoma (82.4%). Twelve patients had distant metastasis (70.6%). Various treatments were administered to the patients prior to ICI and RT combination treatment. The 6-month overall survival and progression-free survival was 62.7% and 26.5%, respectively. The 6-month in-field control rate was 67.4% and 6-month out-field control rate was 26.6%. Higher BED (≥ 90 Gy) was a significant prognostic factor for both in-field and out-field control, and lymphopenia (≤ 800 /μL) at the time of RT start was a poor prognostic factor for outfield control. Fractional dose of less than 5 Gy showed improved in-field and out-field control. Treatment related toxicity occurred in 10 patients (58.8%). The most frequent adverse event was GI disorders such as esophagitis (n = 3) and epigastric pain (n = 3). Patients who experienced treatment-related toxicity were well recovered after conservative care. There was no grade 3 or 4 toxicity. Conclusions: The combination of ICI and RT showed substantial efficacy with acceptable toxicity in heavily pretreated advanced hepatobiliary cancer patients. Dose per fraction of less than 5 Gy may be appropriate for better efficacy in future study of combining ICI and RT. The results of this study provides a basis for future prospective study in hepatobiliary cancer.

Gut microbiome is associated with the clinical response to anti-PD-1 based immunotherapy in hepatobiliary cancers

BackgroundThe gut microbiome is associated with the response to immunotherapy for different cancers. However, the impact of the gut microbiome on hepatobiliary cancers receiving immunotherapy remains unknown. This study aims...

107P Co-mutation of IDH1 and DNA damage repair genes in patients with hepatobiliary cancer implicates longer overall survival

Hepatobiliary cancer (HBC) is a type of aggressive disease with poor prognosis and patients with advanced HBC have limited therapeutic options. Genomic characterization for cancer patients by next-generation sequencing has become an effective approach to facilitate the development of target therapy. IDH1 and DNA damage repair genes (DDR) mutations have been identified in HBC patients and they usually indicate a longer overall survival (OS). Here, we for the first time we know revealed the genomic feature of co-mutation patterns of IDH1 and DDR genes in HBC patients in both Western and Chinese populations and compared OS in different mutation pattern.

Symptomatology of Advanced Gastrointestinal and Hepatobiliary Cancers in Palliative Care: Single Center Tertiary Care Experience from Eastern India

The spectrum of symptoms for an oncologist or oncosurgeon about gastrointestinal (GI) and hepatobiliary (HB) cancers varies from the spectrum of symptoms that a palliative care physician ascertains. There is a paucity of data regarding GI and HB cancer symptomatology in a palliative care outset. Hence, we conducted this study to understand the same and identify the most common symptom clusters among these cancers. The present study was retrospective observational study conducted on patients referred to palliative care department of Tata medical center, Kolkata, India. A total of 495 patient’s case records were reviewed with GI and HB cancers. Age, gender, co-morbidities, Eastern Cooperative Oncology Group (ECOG) status, symptomatology, physical examination findings, and histopathological diagnosis were reviewed from the case records and documented. Symptomatology included pain, nausea, vomiting, anxiety, depression, constipation, anorexia, early satiety and loose stools. The mean age of the patients was 57.73 ± 12.50 years with male: female ratio of 1.60. The most common organ system involved was gall bladder (22.63%) followed by pancreas (16.97%). The most common symptom was abdominal pain (63.64%) followed by anorexia (28.08%) and constipation (21.62%) and the least common ones were loose stools (3.84%) and neuropsychiatric symptoms (4.85%). Nausea-vomiting cluster (38.10%) and abdominal pain-nausea/vomiting (28.38%) cluster were most common among stomach carcinomas. Abdominal pain-constipation cluster (23.21%) was more common among gall bladder carcinomas. Future studies directing to identify these symptoms and clusters over the quality of life of advanced cancer patients are warranted.

Hepatic Arterial Infusion of Chemotherapy for Advanced Hepatobiliary Cancers: State of the Art.

Simple SummaryLiver functional failure is one of the leading causes of cancer-related death. Systemic chemotherapy usually offers a modest benefit in terms of disease control rate, progression-free survival, and overall survival at the cost of a significant percentage of adverse events. Liver malignancies are mostly perfused by the hepatic artery while the normal liver parenchyma by the portal vein network. On these bases, the therapeutic strategy consisting of hepatic arterial infusion of chemotherapy takes place. This review aims to summarize the current knowledge on this approach from different points of view, such as techniques, drugs pharmacology and pharmacokinetics, and clinical outcomes for advanced hepatobiliary cancers. Most of the collected studies have several limitations: non-randomized retrospective design, a relatively small number of patients, the hepatic arterial administration of different chemotherapeutic agents, as well as its combination with a great heterogeneity of systemic agents. However, despite these limitations, the presented data show favorable results in terms of safety and efficacy for hepatic arterial infusion of chemotherapy, with respect or in alternative to the gold standard treatment, even when they are combined with systemic treatments. Therefore, this therapeutic strategy may be an alternative or an integrative treatment option for advanced hepatobiliary cancers. Further and larger prospective, randomized, multi-center studies, with well-defined inclusion criteria and treatment strategies, are required to confirm the presented data.Liver functional failure is one of the leading causes of cancer-related death. Primary liver tumors grow up mainly in the liver, and thus happens for liver metastases deriving from other organs having a lower burden of disease at the primary site. Systemic chemotherapy usually offers a modest benefit in terms of disease control rate, progression-free survival, and overall survival at the cost of a significant percentage of adverse events. Liver malignancies are mostly perfused by the hepatic artery while the normal liver parenchyma by the portal vein network. On these bases, the therapeutic strategy consisting of hepatic arterial infusion (HAI) of chemotherapy takes place. In literature, HAI chemotherapy was applied for the treatment of advanced hepatobiliary cancers with encouraging results. Different chemotherapeutic agents were used such as Oxaliplatin, Cisplatin, Gemcitabine, Floxuridine, 5-Fluorouracil, Epirubicin, individually or in combination. However, the efficacy of this treatment strategy remains controversial. Therefore, this review aims to summarize the current knowledge on this approach from different points of view, such as techniques, drugs pharmacology and pharmacokinetics, and clinical outcomes for advanced hepatobiliary cancers.

Laparoscopic portal branch ligation of the right caudate lobe concomitant with portal vein embolization for planned right hemihepatectomy in advanced hepatobiliary cancers.

The role of ligation of the portal venous branches to the caudate lobe (cPVL) as preparation for planned major hepatectomy is unclear. The aim of this study was to evaluate the efficacy of laparoscopic cPVL (Lap-cPVL) concomitant with transileocolic portal vein embolization of the right portal venous system (rTIPE), namely, Lap-cPVL/rTIPE, for planned right hemihepatectomy (rHx) in advanced hepatobiliary cancer patients. Thirty-one patients who underwent rHx after rTIPE with/without Lap-cPVL between March 2013 and March 2020 were enrolled in this study. The Lap-cPVL was performed for the portal branches of the right caudate lobe. Eight of the 31 patients underwent Lap-cPVL/rTIPE. The degree of hypertrophy was significantly increased in Lap-cPVL/rTIPE (19.3%, range 6.5-25.6%) as compared to rTIPE (7.2%, range - 1.1 to 21.2%) (p=0.027). The functional kinetic growth rate was also significantly increased in Lap-cPVL/rTIPE (5.40%, range 2.17-5.97) than that in rTIPE (1.85%, range - 0.22 to 6.45%) (p=0.046). Postoperative liver failure ≧ grade B occurred in 21.7% of patients in rTIPE, while there was no postoperative liver failure ≧ grade B in Lap-cPVL/rTIPE. Mortality rates were zero after rHx in this study. Lap-cPVL/rTIPE is safe and provides an additional effect on liver hypertrophy in advanced hepatobiliary cancers.

Hybrid transileocecal portal vein embolization associated with staging laparoscopy for planned major hepatectomy in advanced hepatobiliary cancers.

Portal vein embolization (PVE) is widely used to promote the hypertrophy of a future liver remnant (FLR) and reduce posthepatectomy liver failure. The aim of this study was to evaluate the efficacy of transileocecal portal embolization (TIPE) associated with staging laparoscopy (hybrid lap-TIPE) for a planned hepatectomy in advanced hepatobiliary cancers. The hybrid lap-TIPE procedure consisted of staging laparoscopy for complete screening of the abdominal cavity with cytoreductive surgery and subsequent TIPE. Data on hybrid lap-TIPE, performed between March 2013 and February 2020, were collected retrospectively. Hybrid lap-TIPE was conducted for 52 patients, and a subsequent TIPE was accomplished in 42 patients (80.8%), since staging laparoscopy detected latent or unresectable factors in 13 patients (25.0%), among which 2 patients with hepatocellular carcinoma and 1 with colorectal liver metastasis received laparoscopic cytoreductive surgery for latent lesions in the FLR. Finally, radical hepatectomy was completed in 36 patients (69.2%), including 3 patients who underwent cytoreductive surgery. The most common operation was an extended right hepatectomy (50.0%), followed by right hepatectomy (30.6%), including 3 hepatopancreatoduodenectomies. The overall morbidity associated with hybrid lap-TIPE and hepatectomy was 7.1% and 41.7%, respectively. The mortality associated with hybrid lap-TIPE and hepatectomy was 0% and 5.6%, respectively. The rates of 2-year survival and 2-year disease-free survival were 64.8% and 61.9%, respectively, after hepatectomy. Hybrid lap-TIPE is safe and could be a useful treatment option for patients with advanced hepatobiliary cancer because it can help to identify optimal candidates for PVE followed by a planned hepatectomy.

Immunotherapy utilization for hepatobiliary cancer in the United States: disparities among patients with different socioeconomic status.

Patients with advanced hepatobiliary cancer (HBC) have a dismal prognosis and limited treatment options. Immunotherapy has been considered as a promising treatment, especially for cancers not amenable to surgery. Between 2004, and 2015, patients diagnosed with hepatocellular carcinoma (HCC), intra- and extrahepatic cholangiocarcinoma and gallbladder cancer (GBC) were identified in the National Cancer Database. Among 249,913 patients with HBC, only 585 (0.2%) patients received immunotherapy. Among patients who received immunotherapy, most patients were diagnosed between 2012 and 2015, had private insurance, as well as an income ≥$46,000 and were treated at an academic facility. The use of immunotherapy among HBC patients varied by diagnosis (HCC, 67.7%; bile duct cancer, 14%). On multivariable analysis, a more recent period of diagnosis (OR 1.80, 95% CI: 1.44-2.25), median income >$46,000 (OR 1.43, 95% CI: 1.11-1.87), and higher tumor stage (stage III, OR 2.22, 95% CI: 1.65-3.01; stage IV, OR 3.24, 95% CI: 2.41-4.34) were associated with greater odds of receiving immunotherapy. Overall utilization of immunotherapy in the US among patients with HBC was very low, yet has increased over time. Certain socioeconomic factors were associated with an increased likely of receiving immunotherapy, suggesting disparities in access of patients with lower socioeconomic status.

Novel immunotherapy strategies for hepatobiliary cancers.

Despite recent advancements in therapeutic options for advanced hepatobiliary cancers, there remains an unmet need for innovative systemic treatments. Immunotherapy has shown an ability to provide prolonged clinical benefit, but this benefit remains limited to a small subset of patients. Numerous ongoing endeavors are investigating novel immunotherapy concepts. Immunotherapies that have demonstrated clinical efficacy in hepatobiliary cancers includePD-1 inhibitor therapy andCTLA-4 inhibitor therapy. Novel immunotherapy concepts include targeting emerging checkpoint proteins, bispecific T-cell engagers, combinatorial trials with checkpoint inhibitors, oncolytic virotherapy and chimeric antigen receptor T cells. The goal for these new treatment strategies is to achieve a meaningful expansion of patients deriving prolonged clinical benefit from immunotherapy.

Exploring the role of oncolytic viruses in hepatobiliary cancers.

The standard of care for early hepatobiliary cancers (HBC) includes surgical resection. Liver transplantations or locoregional therapies are beneficial in early hepatocellular carcinoma (HCC) under certain circumstances. Systemic treatments have some benefit in advanced HBC, though long-term prognosis remains poor. We evaluated the role of oncolytic viruses in the treatment of HBCs through a systematic literature review. The recombinant vaccinia virus JX-594 improved median survival in patients with local/metastatic HCC more strongly at high dose than at low dose (14.1 vs 6.7 months; p=0.08) in a Phase II study. A Phase III study with JX-594 and sorafenib in advanced HCC is ongoing. No survival benefit in HCC was seen with two other recombinant adenoviruses (Ad-TK and DL1520). Several preclinical trials using oncolytic viruses in HBC showed promising results, warranting clinical studies.

Significance of serum ferritin as a prognostic factor in advanced hepatobiliary cancer patients treated with Korean medicine: a retrospective cohort study

BackgroundAdvanced hepatobiliary cancers are highly lethal cancers that require precise prediction in clinical practice. Serum ferritin level increases in malignancy and high serum ferritin level is associated with poor survival in various cancers. This study aimed to identify whether serum ferritin could independently predict the overall survival (OS) of patients with advanced hepatobiliary cancers.MethodsThe retrospective cohort study was performed by reviewing medical records of patients with advanced hepatobiliary cancers from June 2006 to September 2016. The demographic and clinicopathological characteristics as well as the biochemical markers were evaluated at the initiation of Korean medicine (KM) treatment. The OS was calculated using Kaplan-Meier estimates. The Cox proportional hazard model was used to identify the independent prognostic significance of serum ferritin for survival.ResultsThe median OS of all subjects was 5.1 months (range, 0.5–114.9 months). The median OS of group with low ferritin levels and that with high ferritin levels was 7.5 months (range, 0.7–114.9 months) and 2.8 months (range, 0.5–22.8 months), respectively (P < 0.001). The results of the univariate analysis showed that the Eastern Cooperative Oncology Group Performance Status (ECOG-PS) (P = 0.002), tumor type (P = 0.001), prior treatment (P = 0.023), serum ferritin (P < 0.001), hemoglobin (P = 0.002), total bilirubin (P = 0.002), gamma-glutamyl transpeptidase (P = 0.007), albumin (P = 0.013), white blood cell (P = 0.002), and C-reactive protein (CRP) (P < 0.001) were significant factors for the patients’ survival outcome. On multivariate analysis controlling confounding factors, ferritin (P = 0.041), CRP (P = 0.010), ECOG-PS (P = 0.010), and tumor type (P = 0.018) were identified as independent prognostic factors for survival.ConclusionsThese results indicate that serum ferritin is a valid clinical biochemical marker to predict survival of patients with advanced hepatobiliary cancers.

Potential Efficacy of Allergen Removed Rhus Verniciflua Stokes Extract to Maintain Progression-Free Survival of Patients With Advanced Hepatobiliary Cancer

Hepatobiliary cancers are among the leading causes of cancer-related deaths worldwide. Most of the early-stage, surgically resectable cases show recurrence, and when they do, the prognosis is dismal with limited available treatment options. Here, we report three patients with relapsed hepatobiliary cancers who presented relatively long progression-free survival with the administration of a natural product, allergen removed Rhus verniciflua Stokes (RVS) extract. After commencement of RVS extract, they were progression-free for over 56 months in one case of recurred cholangiocarcinoma, and for over 16 and 114 months respectively, in two cases of advanced hepatocellular carcinoma. These cases suggest that the RVS extract could be a potential alternative for advanced hepatobiliary cancer that has no other available treatment.

Chemotherapy in patients with hepatobiliary cancers and abnormal hepatic function.

Sorafenib and cisplatin plus gemcitabine currently represent first-line treatment standards in advanced hepatocellular carcinoma and biliary cancer, respectively. Conventional cytotoxic agents (monotherapy or combination therapy) have demonstrated activity in the second-line setting or in those in which first-line agents are contraindicated. A strategy for safe yet effective administration of such systemic therapies in patients with advanced hepatobiliary cancer and abnormal liver function needs to be strongly considered. Here, we highlight the safety and tolerability of systemic therapies routinely used for the treatment of advanced hepatobiliary cancer in patients with hepatic dysfunction. Based on data from available clinical studies, we review dosing strategies recommended for chemotherapy and targeted therapy in those with liver dysfunction. Dose modifications for many agents in this population remain empiric due to limited clinical evidence. Future dedicated phase I studies are needed to provide further dosing considerations for combination therapy in those with abnormal liver function in which data is lacking.

The role of surgical clips in the evaluation of interfractional uncertainty for treatment of hepatobiliary and pancreatic cancer with postoperative radiotherapy.

PurposeTo evaluate the utility of implanted surgical clips for detecting interfractional errors in the treatment of hepatobiliary and pancreatic cancer with postoperative radiotherapy (PORT).Methods and MaterialsTwenty patients had been treated with PORT for locally advanced hepatobiliary or pancreatic cancer, from November 2014 to April 2016. Patients underwent computed tomography simulation and were treated in expiratory breathing phase. During treatment, orthogonal kilovoltage (kV) imaging was taken twice a week, and isocenter shifts were made to match bony anatomy. The difference in position of clips between kV images and digitally reconstructed radiographs was determined. Clips were consist of 3 proximal clips (clip_p, ≤2 cm) and 3 distal clips (clip_d, >2 cm), which were classified according to distance from treatment center. The interfractional displacements of clips were measured in the superior-inferior (SI), anterior-posterior (AP), and right-left (RL) directions.ResultsThe translocation of clip was well correlated with diaphragm movement in 90.4% (190/210) of all images. The clip position errors greater than 5 mm were observed in 26.0% in SI, 1.8% in AP, and 5.4% in RL directions, respectively. Moreover, the clip position errors greater than 10 mm were observed in 1.9% in SI, 0.2% in AP, and 0.2% in RL directions, despite respiratory control.ConclusionQuantitative analysis of surgical clip displacement reflect respiratory motion, setup errors and postoperative change of intraabdominal organ position. Furthermore, position of clips is distinguished easily in verification images. The identification of the surgical clip position may lead to a significant improvement in the accuracy of upper abdominal radiation therapy.